If I had only known:  Congenital CMV infection prevention, diagnosis, and treatment

Cytomegalovirus (CMV) is the most common congenital infection and a leading cause of non-genetic hearing loss and other neurologic sequelae, including microcephaly, developmental delay, and vision impairment. An estimated 30,000 infants per year (∼0.7% of all live births) in the U.S. are born with congenital CMV infection, and nearly 20% have at birth or will develop permanent neurologic effects due to CMV. ¹ Death occurs in about 4% of children with symptomatic infection. ²

Most (87%) infants with congenital CMV infection are asymptomatic at birth, but a significant fraction (13%) are symptomatic with hearing loss, hepatosplenomegaly, thrombocytopenia, structural brain malformations, or other abnormalities. With observable clinical signs, these infants can be diagnosed and provided appropriate medical care.  However, those without symptoms appear normal at birth, so miss the opportunity for early diagnosis and close monitoring for late onset hearing loss or neurodevelopmental delay.  With these potential long-term medical conditions, congenital CMV infection carries a similar or higher overall disease burden as more familiar childhood conditions, such as  Down syndrome, fetal alcohol syndrome, or spina bifida.  However,  newborn CMV testing is not routinely peformed, ¹ and most (61·0% to 87·5%) pregnant women are not aware of congenital CMV infection prevention or potential risk in pregnancy. ³ In fact, the initial response of many women after hearing about the diagnosis of their new baby is “If I had only known … No one told me.”Current and future strategies to reduce the burden of congenital CMV infection are discussed.

Prevention

Several CMV vaccines are under development but not currently available. Until a vaccine is licensed, preventive strategies aimed at reducing transmission by increasing public awareness of congenital CMV and promoting minor behavioral changes during pregnancy are being used, particularly by advocacy groups led by parents of CMV affected children.  Young children typically acquire CMV from their peers and shed high levels of virus in saliva, urine, and other bodily fluids without apparent symptoms. Pregnant women, who have and/or work with young children, especially in group daycare settings, are at the highest risk of infection. Avoiding contact with body fluids of young children can substantially reduce this risk, and includes behaviors such as using gloves and hand washing after changing diapers or touching saliva or nasal secretions, not sharing cups or utensils, not kissing on the mouth or cheek, and avoiding co-sleeping.  Women should also be encouraged to use barrier methods to decrease the risk of sexual transmission.In the U.S., some states already require CMV education as part of routine antenatal care. At a minimum, all clinicians caring for women of childbearing age should be fully informed about congenital CMV prevention and have appropriate tools for educating their patients.  While completely eliminating exposure to CMV during pregnancy may not be feasible, exposures and therefore the risk of acquiring CMV can be significantly reduced.¹

Diagnosis of maternal infection

Universal screening of pregnant women with CMV IgG and IgM is not recommended in any country, since the IgG result does not change patient management (i.e., all women benefit from CMV education regardless of CMV serostatus), and positive IgM is uncommon, often false, and may lead to confusion or unnecessary testing. Although women with positive CMV IgG may have a lower risk of CMV infection (actual risk is unknown) or fetal transmission, re-infection with the new virus may be as threatening for the fetus as primary infection.In industrialized countries, up to 50% women of childbearing age are CMV seronegative.² These women are at the highest risk of fetal transmission following primary infection during pregnancy, but are typically asymptomatic. A minority of women may experience symptoms similar to a flu-like illness or mononucleosis, including fever, malaise, myalgia, cervical lymphadenopathy and less commonly, hepatitis or pneumonia.  Pregnant women with symptoms not attributable to another cause or imaging consistent with fetal infection should be offered CMV-specific testing, including IgM, IgG, and (if IgG-positive) IgG avidity to evaluate these abnormalities.3 The detection of CMV IgM associated with negative IgG or low–moderate IgG avidity are indicators of recent primary infection.To minimize the risk of CMV transmission in a non-pregnant woman diagnosed with primary CMV infection, it is recommended that she defer pregnancy until CMV IgM antibody clears and IgG is detectable with high avidity index,⁴ which may take 6-12 months.

Intrauterine Transmission

The risk of CMV transmission from the pregnant woman to the fetus is much greater for primary (30%-35%) versus non-primary (1.4%) CMV infection.² Maternal infection and adaptive immune response prior to conception appear to offer substantial protection against congenital infection, most likely due to the ability of existing antibodies and memory T-cells to control viremia relatively quickly.² However, pre-conception immunity does not provide complete protection from transmission. Women who are CMV-seropositive are at risk of reinfection with a new virus or reactivation of the original virus, either of which could lead to fetal transmission and symptomatic infection.

Prenatal diagnosis of fetal cytomegalovirus infection

For pregnant women with abnormalities on ultrasound or MRI that are compatible with fetal CMV infection, prenatal diagnosis may be considered using culture or nucleic assay detection in amniotic fluid.³  Since the virus is excreted in fetal urine into the amniotic fluid, the highest sensitivity of testing is achieved after 20–21 weeks’ gestation when fetal urination is well established, and at least 6 weeks from the time of maternal CMV infection.

Treatment of the cytomegalovirus-infected fetus during pregnancy

Management options for the infected fetus are limited. Therapies being evaluated include CMV hyperimmune globulin and antiviral drugs such as acyclovir, valacyclovir, and famciclovir.³

Diagnosis of neonatal infection

Clinical features of congenital CMV at birth include jaundice, petechial rash, hepatosplenomegaly, microcephaly, small size for gestational age, and many others, although these findings are not specific for CMV infection.^5,6  However, most infected infants have no or subclinical manifestations at birth, so remain undiagnosed in the absence of newborn screening programs.⁷ Nearly 10%-15% of these initially asymptomatic neonates develop hearing loss or other neurologic abnormalities later, so lack of neonatal CMV diagnosis significantly limits the benefits of early detection.Utah is the first state that implemented a law mandating CMV testing for infants who fail the newborn hearing screen (NBHS).⁴ Connecticut and Iowa were next to follow the Utah example. Illinois requires that a CMV test be offered for every child who fails the hearing screen. Eight states require CMV education for the public and professionals: Colorado, Hawaii, Idaho, Illinois, Iowa, Oregon, Texas, and Utah. Tennessee requires healthcare providers to educate women of childbearing age.Congenital CMV must be diagnosed within 3 weeks of age, after which post-natal infection is a possible cause of a positive test.  Molecular testing by real-time PCR of saliva or urine is now used routinely instead of rapid culture. A multi-center study reported that real-time PCR of saliva showed high sensitivity (>97%) and specificity (99%) for detecting congenital CMV infection.⁸ A positive saliva CMV PCR should be confirmed by testing a urine sample within 3 weeks of age.3 NBHS-based CMV testing allows for diagnosis in those with possible hearing loss, but fails to detect at least 40% of infected asymptomatic infants.9 Recent studies have  shown that both NBHS-based and universal CMV testing strategies are cost-effective.^5,10

Treatment of congenitally infected neonates

Valganciclovir for 6 months is recommended for neonates with moderate-to-severe clinical manifestations of infection based on evidence that treatment can reduce or prevent progression of hearing loss and improve neurodevelopmental outcomes.³Due to potential toxicity of valganciclovir and lack of clinical trials showing benefit compared to risk, treatment of infants with no/mild symptoms or with hearing loss only is not currently recommended. Several studies to address these populations are in process.

Summary

At a time when neither a CMV vaccine nor highly effective fetal or neonatal interventions are available, CMV awareness and education about safer behaviors during pregnancy are critical to minimize the risk of maternal infection and fetal transmission. Universal CMV screening would provide all infected infants with access to monitoring and interventions that improve outcomes regardless of disease severity.  Development of quick and reliable real-time PCR assays for saliva and urine samples has made implementation of universal newborn CMV screening feasible.References:

1. Cannon JM. Congenital cytomegalovirus (CMV) epidemiology and awareness. Journal of Clinical Virology 46S (2009) S6–S10
2. Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. The "silent" global burden of congenital cytomegalovirus. Clin Microbiol Rev. 2013 Jan; 26(1):86-102
3. Rawlinson, et al., Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy Lancet Infect Dis 2017; 17: e177–88.
4. National CMV Foundation 2018
5. Cannon M, Griffiths P, Aston V, and Rawlinson W. Universal newborn screening for congenital CMV infection: what is the evidence of potential benefit? Rev Med Virol. 2014; 24(5): 291–307.
6. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol 2007; 17(4):253–76.
7. Khalil A, Heath P, Jones C, Soe A, Ville YG on behalf of the Royal College of Obstetricians and Gynecologists. Congenital Cytomegalovirus Infection: Update on Treatment. BJOG 2018;125:e1–e11.
8. Boppana SB, Ross SA, Shimamura M, et al. Saliva polymerase-chain-reaction assay for cytomegalovirus screening in newborns. N Engl J Med 2011;
9. Fowler BK, et al. A Targeted Approach for Congenital Cytomegalovirus Screening Within Newborn Hearing Screening PEDIATRICS 2017; 139 (2)
10. Gantt S, Dionne F, Kozak FK, et al. Cost-effectiveness of universal and targeted newborn screening for congenital cytomegalovirus infection. JAMA Pediatr 2016; 170: 1173–80.